General Description
Yellow-orange to orange crystalline powder; orange-brown chunky solid.
Reactivity Profile
An organic acid and unsaturated aliphatic hydrocarbon. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions.
Air & Water Reactions
Insoluble in water.
Fire Hazard
Flash point data for this material are not available; however, CIS-RETINOIC ACID is probably combustible.
Description
The original patent for Accutane expired in 2002. Held by
Hoffmann-LaRoche until that time, it is perhaps now better
known by its common name, isotretinoin, although over 100
trade names for the compound now exist. Isotretinoin was
originally developed to treat cystic acne, and today this is still
its primary use despite several more modern applications of
the drug, including a treatment for pancreatic and brain
cancers.
Isotretinoin is the 9-cis isomer of retinoic acid, a close
relative of retinol, or vitamin A. First shown to be an effective
treatment for acne in 1982, its development stemmed from
advances in knowledge of the effects of vitamin A to reduce or
eliminate sebum production. Since that time, however, several
instances of deleterious effects became well known, most
notably birth defects arising from the use of isotretinoin.
Accutane was removed from distribution by Roche in 2009
after several lawsuits had been filed alleging damages due to
side effects, especially in young adult males due to inflammatory
bowel disease (IBD).
Chemical Properties
Yellow or orange crystalline powder or crystal, insoluble in water, slightly soluble in ethanol, very slightly soluble in ether, soluble in chloroform.
Originator
Accutane,Roche
Definition
ChEBI: A retinoic acid that is all-trans-retinoic acid in which the double bond which is alpha,beta- to the carboxy group is isomerised to Z configuration. A synthetic retinoid, it is used for th
treatment of severe cases of acne and other skin diseases.
Indications
Isotretinoin (Accutane) alters keratinization in the
acroinfundibulum of sebaceous glands and shrinks
them, thereby reducing sebum excretion and comedogenesis.
These features underlie its usefulness in acne
vulgaris, since sebum secretion is a hallmark of acneprone
skin. Furthermore, the drug has antiinflammatory
activity.
Preparation
Preparation of isotretinoin in a single step from β-ionone and ethyl chloride are first reacted together after which the product is further reacted with triphenylphosphine to obtain Triphenyl salt. The Triphenyl salt is further reacted with cyclopentenone derivative to produce isotretinoin and its 8Z isomer. separate out the 8Z isomer and convert it to isotretinoin through isomerization with the help of nitric acid.
Manufacturing Process
Under an atmosphere of nitrogen, a solution of n-butyl lithium in hexane (321
ml, 15%) was added to a solution of diisopropylamine (48.6 g, 0.48 mole) in
tetrahydrofuran (1000 ml) at -30°C and the mixture was stirred for one hour.
The reaction mixture was then cooled to -72°C and methyl 3,3-dimethyl
acrylate (55 g, 0.48 mole) was added to it. Stirring was continued at -65° to -
75°C for 30 min. To the resulting mixture, a solution of β-ionylidene
acetaldehyde (100 g, 0.458 mole, 9-trans content: 80%) was added and the
reaction mixture was stirred at -65° to -75°C for 1 h. The reaction mixture
was then warmed to 40°C and stirred at this temperature for 3 h. Solvent was
removed under vacuum and the reaction mixture was diluted with water (700
ml) and methanol (300 ml). Activated charcoal (4 g) was then added and the
mixture was refluxed for 30 min. The heterogeneous mixture was filtered
through hyflo and the hyflo bed was washed with methanol (300 ml) and
water (150 ml). The aqueous methanolic layer was then extracted with
hexanes (2 x 500 ml) and acidified with 10% sulfuric acid to pH 2.80.5. The
desired product was then extracted with dichloromethane (2 x 500 ml). The
combined dichloromethane layer was washed with water (2 x 300 ml) and
concentrated in vacuo to afford the desired isotretinoin. Crystallization from
methanol (200 ml) afforded isotretinoin (44 g) in greater than 99% HPLC
purity.
Brand name
Accutane (Roche); Amnesteem
(Genpharm); Claravis (Barr); Sotret (Ranbaxy);Accutane roche;Apsor;Isotretinoin;Neovamin a acid;Neovitamin a acid;Ro 4-3780;Roacutan.
Therapeutic Function
Antiacne, Keratolytic
World Health Organization (WHO)
Isotretinoin, a retinol derivative, was introduced in 1982 exclusively for the treatment of severe acne. Its use in pregnant women has
resulted in major fetal abnormalities. The manufacturer's information emphasizes
that the drug is teratogenic and must not be given to women who are pregnant,
and that contraceptive measures must be maintained for at least four weeks after
discontinuation of treatment. In some countries, blood banks are advised not to
accept as donors persons who have taken isotretinoin within the previous four
weeks. See also under retinol (vitamin A).
Biochem/physiol Actions
13-cis-Retinoic acid (RA) has anti-inflammatory and anti-tumor action. The action of RA is mediated through RAR-β and RAR-α receptors. RA attenuates iNOS expression and activity in cytokine-stimulated murine mesangial cells. It induces mitochondrial membrane permeability transition, observed as swelling and as a decrease in membrane potential, and stimulates the release of cytochrome c implicating mechanisms through the apoptosis pathway. These activities are reversed by EGTA and cyclosporin A. RA also increases MMP-1 protein expression partially via increased transcription.
Mechanism of action
Isotretinoin is rapidly absorbed orally, with peak
blood concentrations 3 hours after ingestion. It is not
stored in tissue, and the elimination half-life is 10 to 20
hours, either after a single dose or during chronic therapy.
Clinical Use
Isotretinoin is most useful for the treatment of severe
recalcitrant nodular acne vulgaris. It may also be helpful in other disorders of keratinization, but it is
not useful for psoriasis. High doses of isotretinoin
(2mg/kg/day) are effective as cancer chemoprevention
agents to reduce the frequency of cutaneous malignancies
in patients at increased risk, such as those with xeroderma
pigmentosum, an inherited disorder in which
DNA repair is deficient, or in immunosuppressed patients.
Side effects
Isotretinoin is teratogenic to humans and should not be administered to pregnant women or women contemplating pregnancy. Concomitant use of isotretinoin with drugs of the tetracycline class increases the incidence of Pseudotumor cerebri. There have been recent reports of an increased risk of depression, suicide, and suicide attempts in individuals taking isotretinoin, but the causality has not been absolutely proved.
Isotretinoin, like many retinoids, can lead to increase in serum aminotransferase levels, but, unlike acitretin and etretinate, isotretinoin has not been clearly implicated in cases of clinically apparent acute liver injury with jaundice.
Veterinary Drugs and Treatments
Isotretinoin may be useful in treating a variety of dermatologicrelated
conditions,
including canine lamellar ichthyosis, cutaneus
T-cell lymphoma, intracutaneous cornifying epitheliomas,
multiple
epidermal inclusion cysts, comedo syndrome in Schnauzers,
and sebaceous adenitis seen in standard poodles.
Because of the concerns of teratogenic effects in humans, availability
to veterinarians may be restricted by the manufacturers and
drug distributors; obtaining the medication for veterinary patients
may be difficult.
Drug interactions
Potentially hazardous interactions with other drugs Antibacterials: possible increased risk of benign intracranial hypertension with tetracyclines - avoid. Antifungals: possible increased risk of toxicity with fluconazole, ketoconazole and voriconazole. Vitamins: increased risk of hypervitaminosis with vitamin A.
Environmental Fate
In primates (including humans), isotretinoin (Accutane) is
metabolized to a more active form, 13-cis-4-oxo-retinoic acid,
which is able to move through the placental membrane. On
its own, however, Accutane (isotretinoin) is not particularly
motile across the placental barrier, and perhaps most interestingly
tends not to bind to cellular retinoid-binding proteins
or nuclear receptors. The rapid isomerization to the all-trans
isomer, the oxidation of Accutane (isotretinoin) to 13-cis-4-
oxo-retinoic acid, and the relatively high circulation times of
these compounds may be important in explaining the teratogenic
toxicity of Accutane (isotretinoin).
Some studies have more fully explored the metabolic
products of isotretinoin. For example, isotretinoin can be
metabolized in the liver by the cytochrome P450 microsomal
enzyme system – more specifically the CYP2C8, CYP2C,
CYP3A4, and CYP2B6 isoenzymes. The metabolites produced
are numerous, including retinoic acid (tretinoin), 4-oxo-isotretinoin,
and 4-oxo-retinoic acid (4-oxo-tretinoin). This relatively
large array of retinoid metabolites may produce a variety
of effects, most notably due to their higher potency as retinoids
compared to the parent compound (isotretinoin).
It is possible that these additional metabolites are capable
of binding to a variety of retinoid receptors in order to alter
gene expression and further transcription or transrepression in
protein synthesis, which may be responsible for the toxic effects
of isotretinoin.
Toxicity evaluation
Direct studies focused on the environmental fate of Accutane
(isotretinoin) are rare in the literature. The pure compound is
insoluble in water, and highly lipophilic. Powders do not
aerosolize readily, and volatilization is extremely low. Isotretinoin
released into the environment would not be expected
to have high mobility in water or soil, and will most likely
become deposited in organic materials. Bioaccumulation is
possible, but isotretinoin is readily oxidized to form other
retinoids or metabolites that are expected to be mitigated via
natural biological pathways.
